Pyrmidine derivatives as selective inhibitors of cox-2

ABSTRACT

The invention provides the compounds of formula (I) and pharmaceutically acceptable derivatives thereof, in which: R 1  and R 2  are independently selected from H, or C 1-6 alkyl, R 3  is C 1-6 alkyl or NH 2 : R 4  is H or C 1-6 alkyl: A is and 5- or 6-membered aryl, or a 5- or 6-membered aryl substituted by one or more R 5 ; R 5  is halogen, C 1-6 alkyl, C 1-6 alkyl substituted by one ore more F, C 1-6 alkoxy, C 1-6 alkoxy substituted by one or more F, SO 2 NH 2  or SO 2 C 1-6 alkyl; and n is 1 to 4. Compounds of formula (I) are potent and selective inhibitors of COX-2 and are of use in the treatment of the pain, fever, inflammation of a variety of conditions and diseases.

[0001] This invention relates to pyrimidine derivatives, to processesfor their preparation, to pharmaceutical compositions containing themand to their use in medicine.

[0002] The enzyme cyclooxygenase (COX) has recently been discovered toexist in two isoforms, COX-1 and COX-2. COX-1 corresponds to theoriginally identified constitutive enzyme while COX-2 is rapidly andreadily inducible by a number of agents including mitogens, endotoxin,hormones, cytokines and growth factors. Prostaglandins generated by theaction of COX have both physiological and pathological roles. It isgenerally believed that COX-1 is largely responsible for the importantphysiological functions such as maintenance of gastrointestinalintegrity and renal blood flow. In contrast the inducible form, COX-2,is believed to be largely responsible for the pathological effects ofprostaglandins where rapid induction of the enzyme occurs in response tosuch agents as inflammatory agents, hormones, growth factors andcytokines. A selective inhibitor of COX-2 would therefore haveanti-inflammatory, anti-pyretic and analgesic properties, without thepotential side effects associated with inhibition of COX-1. We have nowfound a novel group of compounds which are both potent and selectiveinhibitors of COX-2.

[0003] The invention thus provides the compounds of formula (I)

[0004] and pharmaceutically acceptable derivatives thereof, in which:

[0005] R¹ and R² are independently selected from H, or C₁₋₆alkyl;

[0006] R³ is C₁₋₆alkyl or NH₂;

[0007] R⁴ is H or C₁₋₆alkyl;

[0008] A is a 5- or 6-membered aryl, or a 5- or 6-membered arylsubstituted by one or more R⁵;

[0009] R⁵ is halogen, C₁₋₆alkyl, C₁₋₆-alkyl substituted by one or moreF, C₁₋₆alkoxy, C₁₋₆-alkoxy substitued by one or more F, SO₂NH₂ orSO₂C₁₋₆alkyl; and

[0010] n is 1 to 4.

[0011] By pharmaceutically acceptable derivative is meant anypharmaceutically acceptable salt, solvate, ester or amide, or salt orsolvate of such ester or amide, of the compounds of formula (I), or anyother compound which upon administration to the recipient is capable ofproviding (directly or indirectly) a compound of formula (I) or anactive metabolite or residue thereof.

[0012] It will be appreciated by those skilled in the art that thecompounds of formula (I) may be modified to provide pharmaceuticallyacceptable derivatives thereof at any of the functional groups in thecompounds. Of particular interest as such derivatives are compoundsmodified at the benzenesulphonamide function to provide metabolicallylabile benzenesulphonamides. Acylated benzenesulphonamide derivativesare of especial interest.

[0013] It will be appreciated by those skilled in the art that thepharmaceutically acceptable derivatives of the compounds of formula (I)may be derivatised at more than one position.

[0014] It will be further appreciated by those skilled in the art thatbenzenesulphonamide derivatives of formula (I) may be useful asintermediates in the preparation of compounds of formula (I), or aspharmaceutically acceptable derivatives of formula (I), or both.

[0015] It will be appreciated that, for pharmaceutical use, the saltsreferred to above will be the physiologically acceptable salts, butother salts may find use, for example in the preparation of compounds offormula (I) and the physiologically acceptable salts thereof.

[0016] Suitable pharmaceutically acceptable salts include: acid additionsalts formed with inorganic or organic acids, preferably inorganicacids, e.g. hydrochlorides, hydrobromides and sulphates; and alkalimetal salts, formed from addition of alkali metal bases, such as alkalimetal hydroxides, e.g. sodium salts.

[0017] The term halogen is used to represent fluorine, chlorine, bromineor iodine.

[0018] The term ‘alkyl’ as a group or part of a group means a straightor branched chain alkyl group, for example a methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl or t-butyl group.

[0019] The term 5-membered aryl means an aryl selected from thefollowing:

[0020] The term 6-membered aryl means aryl selected from:

[0021] It will be appreciated by those skilled in the art that when R¹and R² in formula (I) are different the corresponding compounds containat least one chiral centre, by virtue of the asymmetric carbon atomdefined thereby, and that such compounds exist in the form of a pair ofoptical isomers (i.e. enantiomers).

[0022] It is to be understood that the present invention encompasses allisomers of the compounds of formula (I) and their pharmaceuticallyacceptable derivatives, including all geometric, tautomeric and opticalforms, and mixtures thereof (e.g. racemic mixtures).

[0023] In one aspect of the invention R¹ and R² are independentlyselected from H or methyl. In another aspect R¹ and R² are both H.

[0024] In another aspect of the invention R³ is C₁₋₆alkyl, such asC₁₋₃alkyl (e.g. methyl).

[0025] In another aspect of the invention, R⁴ is H or C₁₋₃alkyl, such asmethyl.

[0026] In another aspect of the invention A is selected from

[0027] and A is unsubstituted or substituted by one or two R⁵ (e.g. oneR⁵).

[0028] In another aspect of the invention A is selected from

[0029] In another aspect of the invention R⁵ is halogen (e.g. F),C₁₋₃alkyl (e.g. methyl), C₁₋₃alkyl substituted by one to three F (e.g.CF₃), C₁₋₃alkoxy (e.g. methoxy), C₁₋₃alkoxy substituted by one to threeF (e.g. OCHF₂ or OCF₃), or SONH₂.

[0030] In another aspect of the invention R⁵ is halogen (e.g. F) orC₁₋₆-alkoxy, such as C₁₋₃alkoxy (e.g. methoxy).

[0031] In another aspect of the invention n is 1 to 3 (e.g. 1).

[0032] It is to be understood that the invention covers all combinationsof particular aspects of the invention as described hereinabove.

[0033] Within the invention there is provided one group of compounds offormula (I) (group A) wherein: R¹ and R² are independently selected fromH or methyl; R³ is C₁₋₆-alkyl, such as C₁₋₃alkyl (e.g. methyl); R⁴ is Hor C₁₋₃alkyl, such as methyl; A is selected from

[0034] and is unsubstituted or substituted by one or two R⁵ (e.g. oneR⁵); R⁵ is halogen (e.g. F), C₁₋₃alkyl (e.g. methyl), C₁₋₃alkylsubstituted by one to three F (e.g. CF₃), C₁₋₃alkoxy (e.g. methoxy),C₁₋₃alkoxy substituted by one to three F (e.g. OCHF₂ or OCF₃), or SONH₂;and n is 1 to 3 (e.g. 1).

[0035] Within the invention there is provided another group of compoundsof formula (I) (group B) wherein: R¹ and R² are independently selectedfrom H or methyl; R³ is C₁₋₆alkyl, such as C₁₋₃alkyl (e.g. methyl); R⁴is H or C₁₋₃alkyl, such as methyl; A is selected from

[0036] R⁵ is halogen (e.g. F), C₁₋₃alkyl (e.g. methyl), C₁₋₃alkylsubstituted by one to three F (e.g. CF₃), C₁₋₃alkoxy (e.g. methoxy),C₁₋₃alkoxy substituted by one to three F (e.g. OCHF₂ or OCF₃), or SONH₂;and n is 1 to 3 (e.g. 1).

[0037] Within the invention there is provided another group of compoundsof formula (I) (group C) wherein: R¹ and R² are independently selectedfrom H or methyl; R³ is C₁₋₆alkyl, such as C₁₋₃alkyl (e.g. methyl); R⁴is H or C₁₋₃alkyl, such as methyl; A is selected from

[0038] R⁵ is halogen (e.g. F) or C₁₋₆alkoxy, such as C₁₋₃alkoxy (e.g.methoxy); and n is 1 to 3 (e.g. 1).

[0039] In another aspect of the invention, R¹ and R² in the compounds ofgroups A, B and C are both H.

[0040] In another aspect the invention provides the following compounds:

[0041]4-[4-(methylsulfonyl)phenyl]-N-(pyridin4-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;

[0042]4-[4-(methylsulfonyl)phenyl]-N-(pyridin-3-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;

[0043]4-[4-(methylsulfonyl)phenyl]-N-(pyridin-2-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;

[0044]4-[4-(methylsulfonyl)phenyl]-N-(phenylmethyl)-6-(trifluoromethyl)-2-pyrimidinamine;

[0045]N-(4-methoxybenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine;

[0046]N-(4-fluorobenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine;

[0047] and pharmaceutically acceptable derivatives thereof.

[0048] Compounds of the invention are potent and selective inhibitors ofCOX-2. This activity is illustrated by their ability to selectivelyinhibit COX-2 over COX-1.

[0049] In view of their selective COX-2 inhibitory activity, thecompounds of the present invention are of interest for use in human andveterinary medicine, particularly in the treatment of the pain (bothchronic and acute), fever and inflammation of a variety of conditionsand diseases mediated by COX-2. Such conditions and diseases are wellknown in the art and include rheumatic fever; symptoms associated withinfluenza or other viral infections, such as the common cold; lower backand neck pain; headache; toothache; sprains and strains; myositis;sympathetically maintained pain; synovitis; arthritis, includingrheumatoid arthritis; degenerative joint diseases, includingosteoarthritis; gout and ankylosing spondylitis; tendinitis; bursitis;skin related conditions, such as psoriasis, eczema, burns anddermatitis; injuries, such as sports injuries and those arising fromsurgical and dental procedures.

[0050] The compounds of the invention are also useful for the treatmentof neuropathic pain. Neuropathic pain syndromes can develop followingneuronal injury and the resulting pain may persist for months or years,even after the original injury has healed. Neuronal injury may occur inthe peripheral nerves, dorsal roots, spinal cord or certain regions inthe brain. Neuropathic pain syndromes are traditionally classifiedaccording to the disease or event that precipitated them. Neuropathicpain syndromes include: diabetic neuropathy; sciatica; non-specificlower back pain; multiple sclerosis pain; fibromyalgia; HIV-relatedneuropathy; neuralgia, such as post-herpetic neuralgia and trigeminalneuralgia; and pain resulting from physical trauma, amputation, cancer,toxins or chronic inflammatory conditions. These conditions aredifficult to treat and although several drugs are known to have limitedefficacy, complete pain control is rarely achieved. The symptoms ofneuropathic pain are incredibly heterogeneous and are often described asspontaneous shooting and lancinating pain, or ongoing, burning pain. Inaddition, there is pain associated with normally non-painful sensationssuch as “pins and needles” (paraesthesias and dysesthesias), increasedsensitivity to touch (hyperesthesia), painful sensation followinginnocuous stimulation (dynamic, static or thermal allodynia), increasedsensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia),continuing pain sensation after removal of the stimulation (hyperpathia)or an absence of or deficit in selective sensory pathways (hypoalgesia).

[0051] The compounds of the invention are also useful for the treatmentof other conditions mediated by COX-2.

[0052] For example, the compounds of the invention inhibit cellular andneoplastic transformation and metastatic tumour growth and hence areuseful in the treatment of certain cancerous diseases, such as coloniccancer and prostate cancer. The compounds of the invention are alsouseful in reducing the number of adenomatous colorectal polyps and thusreduce the risk of developing colon cancer. The compounds of theinvention are also useful in the treatment of cancer associated withoverexpression of HER-2/neu, in particular breast cancer.

[0053] Compounds of the invention also prevent neuronal injury byinhibiting the generation of neuronal free radicals (and hence oxidativestress) and therefore are of use in the treatment of stroke; epilepsy;and epileptic seizures (including grand mal, petit mal, myoclonicepilepsy and partial seizures).

[0054] Compounds of the invention also inhibit prostanoid-induced smoothmuscle contraction and hence are of use in the treatment ofdysmenorrhoea and premature labour.

[0055] Compounds of the invention are also useful in the treatment ofliver disease, such as inflammatory liver disease, for example chronicviral hepatitis B, chronic viral hepatitis C, alcoholic liver injury,primary biliary cirrhosis, autoimmune hepatitis, nonalcoholicsteatohepatitis and liver transplant rejection.

[0056] Compounds of the invention inhibit inflammatory processes andtherefore are of use in the treatment of asthma, allergic rhinitis andrespiratory distress syndrome; gastrointestinal conditions such asinflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome and ulcerative colitis; and the inflammation in such diseasesas vascular disease, migraine, periarteritis nodosa, thyroiditis,aplastic anaemia, Hodgkin's disease, sclerodoma, type I diabetes,myasthenia gravis, multiple sclerosis, sorcoidosis, nephrotic syndrome,Bechet's syndrome, polymyositis, gingivitis, conjunctivitis andmyocardial ischemia.

[0057] Compounds of the invention are also useful in the treatment ofophthalmic diseases such as retinitis, retinopathies, uveitis and ofacute injury to the eye tissue.

[0058] Compounds of the invention are also useful for the treatment ofcognitive disorders such as dementia, particularly degenerative dementia(including senile dementia, Alzheimer's disease, Pick's disease,Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease),and vascular dementia (including multi-infarct dementia), as well asdementia associated with intracranial space occupying lesions, trauma,infections and related conditions (including HIV infection), metabolism,toxins, anoxia and vitamin deficiency; and mild cognitive impairmentassociated with ageing, particularly Age Associated Memory Impairment.

[0059] According to a further aspect of the invention, we provide acompound of formula (I) or a pharmaceutically acceptable derivativethereof for use in human or veterinary medicine.

[0060] According to another aspect of the invention, we provide acompound of formula (I) or a pharmaceutically acceptable derivativethereof for use in the treatment of a condition which is mediated byCOX-2.

[0061] According to a further aspect of the invention, we provide amethod of treating a human or animal subject suffering from a conditionwhich is mediated by COX-2 which comprises administering to said subjectan effective amount of a compound of formula (I) or a pharmaceuticallyacceptable derivative.

[0062] According to a further aspect of the invention, we provide amethod of treating a human or animal subject suffering from aninflammatory disorder, which method comprises administering to saidsubject an effective amount of a compound of formula (I) or apharmaceutically acceptable derivative thereof.

[0063] According to another aspect of the invention, we provide the useof a compound of formula (I) or a pharmaceutically acceptable derivativethereof for the manufacture of a therapeutic agent for the treatment ofa condition which is mediated by COX-2.

[0064] According to another aspect of the invention, we provide the useof a compound of formula (I) or a pharmaceutically acceptable derivativethereof for the manufacture of a therapeutic agent for the treatment ofan inflammatory disorder.

[0065] It is to be understood that reference to treatment includes bothtreatment of established symptoms and prophylactic treatment, unlessexplicitly stated otherwise.

[0066] It will be appreciated that the compounds of the invention mayadvantageously be used in conjunction with one or more other therapeuticagents. Examples of suitable agents for adjunctive therapy include a5HT₁ agonist, such as a triptan (e.g. sumatriptan or naratriptan); anadenosine A1 agonist; an EP ligand (e.g. an EP4 antagonist); an NMDAmodulator, such as a glycine antagonist; a sodium channel blocker (e.g.lamotrigine); a substance P antagonist (e.g. an NK₁ antagonist); acannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; aleukotriene receptor antagonist; a DMARD (e.g. methotrexate); gabapentinand related compounds; a tricyclic antidepressant (e.g. amitryptilline);a neurone stabilising antiepileptic drug; a mono-aminergic uptakeinhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; anitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOSinhibitor; an inhibitor of the release, or action, of tumour necrosisfactor α; an antibody therapy, such as a monoclonal antibody therapy; anantiviral agent, such as a nucleoside inhibitor (e.g. lamivudine) or animmune system modulator (e.g. interferon); an opioid analgesic; a localanaesthetic; a stimulant, including caffeine; an H₂-antagonist (e.g.ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g.aluminium or magnesium hydroxide; an antiflatulent (e.g. simethicone); adecongestant (e.g. phenylephrine, phenylpropanolamine, pseudoephedrine,oxymetazoline, epinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxyephedrine); an antitussive (e.g. codeine,hydrocodone, carmiphen, carbetapentane, or dextramethorphan); adiuretic; or a sedating or non-sedating antihistamine. It is to beunderstood that the present invention covers the use of a compound offormula (I) or a pharmaceutically acceptable derivative thereof incombination with one or more other therapeutic agents.

[0067] The compounds of formula (I) and their pharmaceuticallyacceptable derivatives are conveniently administered in the form ofpharmaceutical compositions. Thus, in another aspect of the invention,we provide a pharmaceutical composition comprising a compound of formula(I) or a pharmaceutically acceptable derivative thereof adapted for usein human or veterinary medicine. Such compositions may conveniently bepresented for use in conventional manner in admixture with one or morephysiologically acceptable carriers or excipients.

[0068] The compounds of formula (I) and their pharmaceuticallyacceptable derivatives may be formulated for administration in anysuitable manner. They may, for example, be formulated for topicaladministration or administration by inhalation or, more preferably, fororal, transdermal or parenteral administration. The pharmaceuticalcomposition may be in a form such that it can effect controlled releaseof the compounds of formula (I) and their pharmaceutically acceptablederivatives.

[0069] For oral administration, the pharmaceutical composition may takethe form of, for example, tablets (including sub-lingual tablets),capsules, powders, solutions, syrups or suspensions prepared byconventional means with acceptable excipients.

[0070] For transdermal administration, the pharmaceutical compositionmay be given in the form of a transdermal patch, such as a transdermaliontophoretic patch.

[0071] For parenteral administration, the pharmaceutical composition maybe given as an injection or a continuous infusion (e.g. intravenously,intravascularly or subcutaneously). The compositions may take such formsas suspensions, solutions or emulsions in oily or aqueous vehicles andmay contain formulatory agents such as suspending, stabilising and/ordispersing agents. For administration by injection these may take theform of a unit dose presentation or as a multidose presentationpreferably with an added preservative.

[0072] Alternatively for parenteral administration the active ingredientmay be in powder form for reconstitution with a suitable vehicle.

[0073] The compounds of the invention may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

[0074] As stated above, the compounds of the invention may also be usedin combination with other therapeutic agents. The invention thusprovides, in a further aspect, a combination comprising a compound offormula (I) or a pharmaceutically acceptable derivative thereof togetherwith a further therapeutic agent.

[0075] The combinations referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical formulations comprising a combination as defined abovetogether with a pharmaceutically acceptable carrier or excipientcomprise a further aspect of the invention. The individual components ofsuch combinations may be administered either sequentially orsimultaneously in separate or combined pharmaceutical formulations.

[0076] When a compound of formula (I) or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art.

[0077] A proposed daily dosage of a compound of formula (I) for thetreatment of man is 0.01 mg/kg to 500 mg/kg, such as 0.05 mg/kg to 100mg/kg, e.g. 0.1 mg/kg to 50 mg/kg, which may be convenientlyadministered in 1 to 4 doses. The precise dose employed will depend onthe age and condition of the patient and on the route of administration.Thus, for example, a daily dose of 0.25 mg/kg to 10 mg/kg may besuitable for systemic administration.

[0078] Compounds of formula (I) and pharmaceutically acceptablederivatives thereof may be prepared by any method known in the art forthe preparation of compounds of analogous structure.

[0079] Suitable methods for the preparation of compounds of formula (I)and pharmaceutically acceptable derivatives thereof follow. In Scheme 1and its variations, R¹ to R⁴, n and A are as defined in formula (I),above unless otherwise stated; Hal is a halogen, such as Cl or Br; MTBEis methyl t-butyl ether; and alkyl is a straight or branched chain alkylgroup, for example a methyl, ethyl, n-propyl, I-propyl, n-butyl, s-butylor t-butyl group.

[0080] Referring to Scheme 1, the treatment of compounds of formula(III) with an amine of formula (II) is conveniently carried out in asolvent, such as a nitrile (e.g. methylnitrile) and at elevatedtemperature (e.g. from about 50° C. to reflux). An excess of the aminemay be used in place of the solvent.

[0081] Conveniently, the boronic acid coupling shown in Scheme 1 iscarried out in a solvent, such as an ether (e.g. 1,2-dimethoxyethane);in the presence of a base, such as an inorganic base (e.g. sodiumcarbonate); and employing a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0).

[0082] Conveniently the oxidation shown in Scheme 1 is effected using amonopersulfate compound, such as potassium peroxymonosulfate (known asOxone™) and the reaction is carried out in a solvent, such as an aqueousalcohol, (e.g. aqueous methanol), and at between −78° C. and ambienttemperature.

[0083] Referring to Scheme 1, the cyclisation of diones of formula (VI)to give the corresponding pyrimidines of formula (IV) is convenientlycarried out employing a thioronium salt such as a2-methyl-2-thiopseudourea sulfate and under reflux.

[0084] It will be appreciated by those skilled in the art that certainof the procedures described in Scheme 1 for the preparation of compoundsof formula (I) or intermediates thereto may not be applicable to some ofthe possible substituents.

[0085] It will be further appreciated by those skilled in the art thatit may be necessary or desirable to carry out the transformationsdescribed in Scheme 1 in a different order from that described, or tomodify one or more of the transformations, to provide the desiredcompound of formula (I).

[0086] In one variation of Scheme 1 (scheme 1A), compounds of formula(III) wherein R³ is C₁₋₆alkyl may be prepared by oxidising a disulphideof formula (IV)A:

[0087] under oxidation conditions described hereinabove. Disulphides offormula (IV)A may be prepared according to the general procedures ofScheme 1 by employing sulphide derivatives in place of the correspondingalkylsulphonyl compounds of formulae (VII) and (VIII).

[0088] In another variation of scheme 1 (scheme 1B), compounds offormula (I) wherein R⁴ is H may be prepared from the correspondingformamyl derivative, as illustrated below.

[0089] It will be appreciated by those skilled in the art that compoundsof formula (I) may be prepared by interconversion, utilising othercompounds of formula (I) as precursors. Suitable interconversions, suchas alkylations, are well known to those skilled in the art and aredescribed in many standard organic chemistry texts, such as ‘AdvancedOrganic Chemistry’ by Jerry March, fourth edition (Wiley, 1992),incorporated herein by reference. For example, compounds of formula (I)wherein R⁴ is C₁₋₆alkyl may be prepared by alkylating the correspondingcompound of formula (I) wherein R⁴ is H.

[0090] Acylation of compounds of formula (I) wherein R³ is NH₂ toprovide corresponding acylated benzenesulphonamide derivatives may becarried out by conventional means, for example by employing conventionalacylating agents such as those described in ‘Advanced OrganicChemistry’, pp 417-424.

[0091] As will be appreciated by those skilled in the art it may benecessary or desirable at any stage in the synthesis of compounds offormula (I) to protect one or more sensitive groups in the molecule soas to prevent undesirable side reactions. The protecting groups used inthe preparation of compounds of formula (I) may be used in conventionalmanner. See, for example, those described in ‘Protective Groups inOrganic Synthesis’ by Theodora W Green and Peter G M Wuts, secondedition, (John Wiley and Sons, 1991), incorporated herein by reference,which also describes methods for the removal of such groups.

[0092] Amines of formula (II) are either known compounds or may beprepared by literature methods, such as those described in‘Comprehensive Organic Transformations: a guide to functional grouppreparations’ by Richard Larock (VCH, 1989), incorporated herein byreference.

[0093] Thioronium salts of formula (V) are either known compounds or maybe prepared by literature methods, such as those described in A H Owenset al, Eur J Med Chem, 1988, 23(3), 295-300, incorporated herein byreference

[0094] Acetophenones of formula (VII) are either known compounds or maybe prepared by conventional chemistry.

[0095] Boronic acids of formula (VIII) or derivatives thereof are eitherknown compounds or may be prepared by literature methods, such as thosedescribed in EPA publication No. 533268; or R Miyaura et al, J Org Chem,1995, 60, 7508-7510; each incorporated herein by reference.

[0096] 4-Halo-6-trifluoromethylpyrimidines of formula (IX) are eitherknown compounds or may be prepared by literature methods, such as thosedescribed in Japanese Patent no. 42014952 (Chem Abs ref CAN 68:105224),incorporated herein by reference.

[0097] Alkyl halides of formula (XII) are either known compounds or maybe prepared by conventional chemistry.

[0098] Certain intermediates described above are novel compounds, and itis to be understood that all novel intermediates herein form furtheraspects of the present invention. Compounds of formulae (III), (IV) and(XIII) are key intermediates and represent a particular aspect of thepresent invention.

[0099] Conveniently, compounds of the invention are isolated followingwork-up in the form of the free base. Pharmaceutically acceptable acidaddition salts of the compounds of the invention may be prepared usingconventional means.

[0100] Solvates (e.g. hydrates) of a compound of the invention may beformed during the work-up procedure of one of the aforementioned processsteps.

[0101] The Intermediates and Examples that follow illustrate theinvention but do not limit the invention in any way. All temperaturesare in ° C. Flash column chromatography was carried out using Merck 9385silica. Solid Phase Extraction (SPE) chromatography was carried outusing Varian Mega Bond Elut (Si) cartridges (Anachem) under 15 mmHgvacuum with stepped gradient elution. Thin layer chromatography (Tlc)was carried out on silica plates. In addition to those already defined,the following abbreviations are used: Me, methyl; Ac, acyl; DMSO,dimethylsulphoxide; TFA, trifluoroacetic acid; DME, dimethoxyethane;THF, tetrahydrofuran; DCM, dichloromethane; and MTBE, methyl t-butylether.

[0102] Intermediate 1

[0103] 4,4,4-Trifluoro-1-[4-(methylthio)phenyl]butane-1,3-dione

[0104] To a solution of ethyl trifluoroacetate (7.95 ml, 1.1eq) in MTBE(125 ml) was added dropwise 25% sodium methoxide in methanol (16 ml,1.2eq). 4-Methylthioacetophenone (Aldrich, 10 g, 0.06 mol) was addedportionwise and the mixture stirred at ambient temperature overnight. 2NHydrochloric acid (40 ml) was added cautiously and the organic phaseseparated, washed with brine and dried (Na₂SO₄) to give an orange solid.The orange solid was recrystallised from hot isopropanol to give thetitle compound as a yellow crystalline solid (11.25 g, 71%).

[0105] MH−261

[0106] Intermediate 2

[0107] 2-(Methylthio)-4-[4-(methylthio)phenyl]-6-(trifluoromethyl)Pyrimidine

[0108] To a mixture of4,4,4-trifluoro-1-[4-(methylthio)phenyl]butane-1,3-dione (5 g) and2-methyl-2-thiopseudourea sulfate (5.1 g, 0.98eq) in acetic acid (100ml) was added sodium acetate (3 g, 2eq) and heated under reflux for 8 h.The mixture was concentrated in vacuo and water (100 ml) added to give asolid, which was isolated by filtration to give the title compound as ayellow solid (5.8 g, quantitative).

[0109] MH+317

[0110] Intermediate 3

[0111] 2-(Methylthio)-4-[4-(methylthio)phenyl]-6-(trifluoromethyl)Pyrimidine

[0112] A mixture of 4-chloro-2-methylthio-6-(trifluoromethyl)pyrimidine(ButtPark Ltd, 2.86 g, 14.55 mmol), 4-(methylthio)phenylboronic acid(Aldrich, 2.83 g, 1.1eq), tetrakistriphenylphosphine palladium (0) (0.2g) and sodium carbonate (4.04 g, 2.6eq) in DME (200 ml) and water (100ml) was heated under reflux with stirring under N₂ for 24 h. Thereaction mixture was concentrated in vacuo and the resultant mixturepartitioned between ethyl acetate and water. The organic phase wasseparated, washed with water, dried (Na₂SO₄) and concentrated in vacuoto a purple solid. Purification by flash column chromatography withcyclohexane:ethyl acetate as (6:1) as eluant gave the title compound asa yellow crystalline solid (3.86 g, 84%).

[0113] MH+317

[0114] Tlc SiO₂ cyclohexane:ethyl acetate (3:1) Rf 0.75 uv₂₅₄

[0115] Intermediate 4

[0116]2-(Methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)Pyrimidine

[0117] To a solution of2-(methylthio)-4-[4-(methylthio)phenyl]-6-(trifluoromethyl) pyrimidine(5.78 g) in MeOH (500 ml) was added a solution of OXONE™ (Aldrich, 56.23g, 5eq) in water (200 ml). The mixture was stirred at ambienttemperature overnight, concentrated in vacuo and the residue partitionedbetween water and ethyl acetate (2×100 ml). The combined organic phaseswere dried and concentrated in vacuo to an off-white solid which wastriturated with hot isopropanol to give the title compound as a whitesolid (5.6 g, 80%).

[0118] MH+381

[0119] Tlc SiO₂ Ethyl acetate:cyclohexane (1:1) Rf 0.45

[0120] Intermediate 5

[0121] 4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine

[0122] A solution of2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine(2 g, 5.258 mmol) in acetonitrile (30 ml) was treated with 0.880 ammonia(6 ml) dropwise. The resulting mixture was then stirred at 20 C for 18h. This gave the title compound as a colourless precipitate which wascollected by filtration and dried (1.53 g)

[0123] MH−=316

[0124] Intermediate 6

[0125]4-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)pyrimidin-2-ylformamide

[0126] A mixture of formic acid (7 ml) and acetic anhydride (2 ml) wasstirred at 20 C for 1 h.4-[4-(Methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine (0.5g, 1.576 mmol) was then added and stirring was continued at ambienttemperature for 18 h. This gave the title compound as a colourlessprecipitate which was collected by filtration and dried (0.32 g).

[0127] MH+=346

[0128] Intermediate 7

[0129](5-methyl-1H-imidazol-4-yl)methyl[4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2yl]formamide

[0130] To a stirred solution of4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-ylformamide(0.5 g, 1.54 mmol) in dry dimethylformamide (10 ml) under N₂ was addedsodium hydride (60% dispersion in oil, 0.16 g). The mixture was stirredfor 30 mins, 4-(chloromethyl)-5-methyl-1H-imidazole, hydrochloride(0.283 g) was added and stirring was then continued at room temp for 18h. The mixture was then partitioned between water and ethyl acetate. Theextracts were dried (Na₂SO₄) and evaporated. The residue was thentriturated with diethyl ether giving the crude title compound as a paleyellow solid (0.27 g).

[0131] MH+=440

EXAMPLE 1

[0132]4-[4-(Methylsulfonyl)phenyl]-N-(pyridin-4-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine

[0133] To a stirred solution of2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-pyrimidine(0.10 g, 0.26 mmol) in MeCN (4 ml) was added 4-(aminomethyl)-pyridine(0.14 ml, 5eq) and the resultant solution heated under reflux for 18 h.The cooled reaction mixture was concentrated in vacuo and purified bySPE chromatography using chloroform, diethyl ether, ethyl acetate,acetone and methanol as the eluotropic series of solvents. Concentrationin vacuo of the combined fractions containing pure product gave thetitle compound as a colourless solid (0.061 g, 57%).

[0134] MH+409.

EXAMPLE 2

[0135]4-[4-(Methylsulfonyl)phenyl]-N-(pyridin-3-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine

[0136] To a stirred solution of2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine(0.10 g, 0.26 mmol) in MeCN (3 ml) was added 3-(aminomethyl)-pyridine(169 mg, 6eq) and the resultant solution heated under reflux for 3 h.The cooled reaction mixture was concentrated in vacuo and the resultingoil purified by SPE chromatography with chloroform thenchloroform:methanol (50:1) as eluant. This gave the title compound as ayellow solid (100 mg, 93%).

[0137] MH+409.

EXAMPLE 3

[0138]4-[4-(Methylsulfonyl)phenyl]-N-(pyridin-2-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amino

[0139] To a stirred solution of2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine(0.10 g, 0.26 mmol) in MeCN (4 ml) was added 2-(aminomethyl)-pyridine(0.14, 5eq) and the resultant solution heated under reflux for 3 h. Thecooled reaction mixture was concentrated in vacuo and purified by SPEchromatography using chloroform, diethyl ether, ethyl acetate, acetoneand methanol as the eluotropic series of solvents. Concentration invacuo of the combined fractions containing pure product gave the titlecompound as a colourless solid (0.086 g, 80%).

[0140] MH+409.

EXAMPLE 4

[0141]4-[4-(Methylsulfonyl)phenyl]-N-(phenylmethyl)-6-(trifluoromethyl)-2-pyrimidinamine

[0142] To a stirred solution of2-(Methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine(0.10 g, 0.26 mmol) in MeCN (4 ml) was added benzylamine (5eq) and theresultant solution heated under reflux for, 24 h. The cooled reactionmixture was concentrated in vacuo and purified by SPE chromatographywith cyclohexane:ethyl acetate (3:1). Concentration in vacuo of thecombined fractions containing pure product gave the title compound as awhite solid (0.090 g, 80%).

[0143] MH+407.

[0144] The Examples of Table 1 were prepared in the manner described forExamples 1 to 4. TABLE 1 (I)

Ex n R¹ R² R³ R⁴ A MS 5 1 (1R)—CH₃ H CH₃ H phenyl MH + 422 6 1 (1S)—CH₃H CH₃ H phenyl MH + 422 7 1 CH₃ CH₃ CH₃ H phenyl MH + 436 8 1 H H CH₃ H3-methoxyphenyl no ion 9 1 H H CH₃ H 4-methoxyphenyl MH + 438 10 1 H HCH₃ H 4-trifluoro- MH + methoxyphenyl 492 11 1 H H CH₃ H3,4-difluorophenyl MH + 444 12 1 H H CH₃ H 4-trifluoro- MH +methylphenyl 476 13 1 H H CH₃ H 4-methylphenyl MH + 422 14 1 H H CH₃ H3-fluorophenyl MH + 426 15 1 H H CH₃ H 4-fluorophenyl MH + 426 16 1 H HCH₃ H 3,5-difluorophenyl MH + 444 17 1 H H CH₃ H 2,5-difluorophenyl MH +444 18 1 H H CH₃ H 2,6-difluorophenyl MH + 444 19 1 H H CH₃ H2,4-difluorophenyl MH+ 444 20 1 H H CH₃ H 4-difluoro- MH + methoxyphenyl474 21 1 H H CH₃ H 3-methylphenyl MH + 422

[0145] TABLE 1 (I)

Ex n R¹ R² R³ R⁴ A¹ MS 22 1 H H CH₃ H 2-fluorophenyl MH + 426 23 1 H HCH₃ H 3-chlorophenyl MH + 442 24 2 H H CH₃ H 2-pyridyl MH + 423 25 1 H HCH₃ H 2-furyl MH + 398 26 1 H H CH₃ CH₃ phenyl MH + 422 27 3 H H CH₃ Hphenyl MH + 426 28 1 H H CH₃ H 5-methyl-2-thienyl MH + 428 29 1 H H CH₃H 4-methyl-2-thiazolyl MH + 429

EXAMPLE 30

[0146]N-(4-methoxybenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine

[0147] A stirred solution of2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine(1 g, 2.629 mmol) in N-methylpyrrolidone (10 ml) was treated with4-methoxybenzylamine (0.69 ml). The mixture was stirred at roomtemperature for 18 h and was then diluted with water (50 ml). This gavea cream solid, which was triturated with diethyl ether giving the titlecompound as a colourless solid (0.98 g).

[0148] MH+=438

EXAMPLE 31

[0149]N-(4-fluorobenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine

[0150] A stirred solution of2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine(1 g, 2.629 mmol) in N-methylpyrrolidone (10 ml) was treated with4-fluorobenzylamine (0.60 ml). The mixture was stirred at room temp for18 h and was then diluted with water (50 ml). This gave the titlecompound as a colourless solid which was collected by filtration anddried (0.72 g).

[0151] MH+=426.

[0152] The Examples of Table 2 were prepared in the manner described forExamples 30 and 31. TABLE 2 (I)

Ex n R¹ R² R³ R⁴ A MS 32 1 H H CH₃ H 1,5-dimethyl-2-pyrrolyl MH + 425 331 H H CH₃ H 3-methyl-2-thienyl MH + 428 34 1 H H CH₃ H 3-thienyl MH +414 35 1 H H CH₃ H 5-methyl-2-furanyl MH + 412 36 1 H H CH₃ H6-methyl-2-pyridyl MH + 423

EXAMPLE 37

[0153]N-[(5-methyl-1H-imidazol-4-yl)methyl]-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine-2-amino

[0154] A solution of crude(5-methyl-1H-imidazol-4-yl)methyl[4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2yl]formamide(0.27 g, 0.615 mmol) in ethanol (10 ml) and 2N hydrochloric acid (10 ml)was heated under reflux for 2 h. The solvents were then evaporated andthe residue basified with 0.880 ammonia and extracted with DCM. Thedried organic phase was evaporated onto silica gel and this mixture waspurified on a silica gel SPE cartridge. Elution with DCM:ethanol:0.880ammonia, 91:8:1, gave the title compound as a colourless crystallinesolid (0.14 g).

[0155] MH+=412.

[0156] The Examples of Table 3 were prepared in the manner described forExample 37. TABLE 3 (I)

Ex n R¹ R² R³ R⁴ A MS 38 1 H H CH₃ H 5-methyl-4-(1H)imidazolyl MH + 41239 1 H H CH₃ H 5-methyl-3-isoxazolyl MH + 413 40 1 H H CH₃ H2-fluoro-4-pyridyl MH + 455

[0157] EXAMPLE 41 Tablets a) Compound of the invention  5.0 mg Lactose95.0 mg Microcrystalline Cellulose 90.0 mg Cross-linkedpolyvinylpyrrolidone  8.0 mg Magnesium Stearate  2.0 mg Compressionweight 200.0 mg 

[0158] The compound of the invention, microcrystalline cellulose,lactose and cross-linked polyvinylpyrrolidone are sieved through a 500micron sieve and blended in a suitable mixer. The magnesium stearate issieved through a 250 micron sieve and blended with the active blend. Theblend is compressed into tablets using suitable punches. b) Compound ofthe invention  5.0 mg Lactose 165.0 mg  Pregelatinised Starch 20.0 mgCross-linked polyvinylpyrrolidone  8.0 mg Magnesium Stearate  2.0 mgCompression weight 200.0 mg 

[0159] The compound of the invention, lactose and pregelatinised starchare blended together and granulated with water. The wet mass is driedand milled. The magnesium stearate and cross-linked polyvinylpyrrolidoneare screened through a 250 micron sieve and blended with the granule.The resultant blend is compressed using suitable tablet punches. EXAMPLE42 Capsules a) Compound of the invention  5.0 mg Lactose 193.0 mg Magnesium Stearate  2.0 mg Fill weight 200.0 mg 

[0160] The compound of the invention and pregelatinised starch arescreened through a 500 micron mesh sieve, blended together andlubricated with magnesium stearate, (meshed through a 250 micron sieve).The blend is filled into hard gelatine capsules of a suitable size. b)Compound of the invention  5.0 mg Lactose 177.0 mg  Polyvinylpyrrolidone 8.0 mg Cross-linked polyvinylpyrrolidone  8.0 mg Magnesium Stearate 2.0 mg Fill weight 200.0 mg 

[0161] The compound of the invention and lactose are blended togetherand granulated with a solution of polyvinylpyrrolidone. The wet mass isdried and milled. The magnesium stearate and cross-linkedpolyvinylpyrrolidone are screened through a 250 micron sieve and blendedwith the granules. The resultant blend is filled into hard gelatinecapsules of a suitable size. EXAMPLE 43 Syrup a) Compound of theinvention  5.0 mg Hydroxypropyl Methylcellulose 45.0 mg PropylHydroxybenzoate  1.5 mg Butyl Hydroxybenzoate 0.75 mg Saccharin Sodium 5.0 mg Sorbitol Solution  1.0 ml Suitable Buffers qs Suitable flavoursqs Purified Water to 10.0 ml

[0162] The hydroxypropyl methylcellulose is dispersed in a portion ofhot purified water together with the hydroxybenzoates and the solutionis allowed to cool to ambient temperature. The saccharin, sodiumflavours and sorbitol solution are added to the bulk solution. Thecompound of the invention is dissolved in a portion of the remainingwater and added to the bulk solution. Suitable buffers may be added tocontrol the pH in the region of maximum stability. The solution is madeup to volume, filtered and filled into suitable containers. EXAMPLE 44Injection Formulation % w/v Compound of the invention  1.00 Water forinjections B.P. to 100.00

[0163] Sodium chloride may be added to adjust the tonicity of thesolution and the pH may be adjusted to that of maximum stability and/orto facilitate solution of the compound of the invention using diluteacid or alkali or by the addition of suitable buffer salts.Solubilisers, such as cosolvents, may also be added to facilitatesolution of the compound of the invention. Antioxidants and metalchelating salts may also be included. The solution is clarified, made upto final volume with water and the pH remeasured and adjusted ifnecessary, to provide 10 mg/ml of the compound of formula (I).

[0164] The solution may be packaged for injection, for example byfilling and sealing in ampoules, vials or syringes. The ampoules, vialsor syringes may be aseptically filled (e.g. the solution may besterilised by filtration and filled into sterile ampoules under asepticconditions) and/or terminally sterilised (e.g. by heating in anautoclave using one of the acceptable cycles). The solution may bepacked under an inert atmosphere of nitrogen.

[0165] Preferably the solution is filled into ampoules, sealed by fusionof the glass and terminally sterilised.

[0166] Further sterile formulations are prepared in a similar mannercontaining 0.5, 2.0 and 5% w/v of the compound of the invention, so asto provide respectively 5, 20 and 50 mg/ml of the compound of theinvention.

[0167] Biological Data

[0168] Inhibitory activity against human COX-1 and COX-2 was assessed inCOS cells which had been stably transfected with cDNA for human COX-1and human COX-2. 24 Hours prior to experiment, COS cells weretransferred from the 175 cm² flasks in which they were grown, onto24-well cell culture plates using the following procedure. Theincubation medium (Dulbecco's modified eagles medium (DMEM) supplementedwith heat-inactivated foetal calf serum (10% v/v), penicillin (100IU/ml), streptomycin (100 μg/ml) and geneticin (600 μg/ml)) was removedfrom a flask of confluent cells (1 flask at confluency containsapproximately 1×10⁷ cells). 10 ml of phosphate buffered saline (PBS) wasadded to the flask to wash the cells. Having discarded the PBS, cellswere then rinsed in 10 ml trypsin for 20 seconds, after which thetrypsin was removed and the flask placed in an incubator (37°) for 1-2minutes until cells became detached from the flask. The flask was thenremoved from the incubator and cells resuspended in 10 ml of freshincubation medium. The contents of the flask was transferred to a 250 mlsterile container and the volume of incubation medium subsequently madeup to 100 ml. 1 ml cell suspension was pipetted into each well of4×24-well cell culture plates. The plates were then placed in anincubator (37° C., 95% air/5% CO₂) overnight. If more than 1 flask ofcells were required, the cells from the individual flasks were combinedbefore being dispensed into the 24-well plates.

[0169] Following the overnight incubation, the incubation medium wascompletely removed from the 24-well cell culture plates and replacedwith 250 μl fresh DMEM (37° C.). The test compounds were made up to250×the required test concentration in DMSO and were added to the wellsin a volume of 1 μl. Plates were then mixed gently by swirling and thenplaced in an incubator for 1 hour (37° C., 95% air/5% CO₂). Followingthe incubation period, 10 μl of arachidonic acid (750 μM) was added toeach well to give a final arachidonic acid concentration of 30 μM.Plates were then incubated for a further 15 minutes, after which theincubation medium was removed from each well of the plates and stored at−20° C., prior to determination of prostaglandin E₂ (PGE2) levels usingenzyme immunoassay. The inhibitory potency of the test compound wasexpressed as an IC₅₀ value, which is defined as the concentration of thecompound required to inhibit the PGE2 release from the cells by 50%. Theselectivity ratio of inhibition of COX-1 versus COX-2 was calculated bycomparing respective IC₅₀ values.

[0170] The following IC₅₀ values for inhibition of COX-2 and COX-1 wereobtained for compounds of the invention: Example No. COX-2: IC₅₀(nM)COX-1: IC₅₀(nM) 1 1.3 >100,000 2 10.8 >100,000 3 2.5 >100,000 40.25 >100,000  9, 30 34 >100,000 15, 31 0.28 >100,000

1. Compounds of formula (I)

and pharmaceutically acceptable derivatives thereof, in which: R¹ and R²are independently selected from H, or C₁₋₆alkyl; R³ is C₁₋₆alkyl or NH₂;R⁴ is H or C₁₋₆alkyl; A is a 5- or 6-membered aryl, or a 5- or6-membered aryl substituted by one or more R⁵; R⁵ is halogen,C₁₋₆-alkyl, C₁₋₆alkyl substituted by one or more F, C₁₋₆alkoxy,C₁₋₆alkoxy substitued by one or more F, SO₂NH₂ or SO₂C₁₋₆alkyl; and n is1 to
 4. 2. Compounds as claimed in claim 1 wherein R¹ and R² areindependently selected from H and methyl.
 3. Compounds as claimed inclaim 1 or 2 wherein R³ is C₁₋₆alkyl, such as C₁₋₃alkyl (e.g. methyl).4. Compounds as claimed in any of claims 1 to 3 wherein R⁴ is H orC₁₋₃alkyl, such as methyl.
 5. Compounds as claimed in any of claims 1 to4 wherein A is selected from

and A is unsubstituted or substituted by one or two R⁵ (e.g. one R⁵). 6.Compounds as claimed in any of claims 1 to 5 wherein R⁵ is halogen (e.g.F), C₁₋₃alkyl (e.g. methyl), C₁₋₃alkyl substituted by one to three F(e.g. CF₃), C₁₋₃alkoxy (e.g. methoxy), C₁₋₃alkoxy substituted by one tothree F (e.g. OCHF₂ or OCF₃), or SONH₂.
 7. Compounds as claimed in anyof claims 1 to 6 wherein n is 1 to 3 (e.g. 1).
 8. Compounds as claimedin any of claims 1 to 7 wherein R¹ and R² are independently selectedfrom H or methyl; R³ is C₁₋₆alkyl, such as C₁₋₃alkyl (e.g. methyl); R⁴is H or C₁₋₃alkyl, such as methyl; A is selected from

and is unsubstituted or substituted by one or two R⁵ (e.g. one R⁵); R⁵is halogen (e.g. F), C₁₋₃alkyl (e.g. methyl), C₁₋₃alkyl substituted byone to three F (e.g. CF₃), C₁₋₃alkoxy (e.g. methoxy), C₁₋₃alkoxysubstituted by one to three F (e.g. OCHF₂ or OCF₃), or SONH₂; and n is 1to 3 (e.g. 1).
 9. Compounds as claimed in any of claims 1 to 8 wherein Ais selected from


10. Compounds as claimed in any of claims 1 to 9 wherein R⁵ is halogen(e.g. F) or C₁₋₆alkoxy, such as C₁₋₃alkoxy (e.g. methoxy).
 11. Compoundsas claimed in any of claims 1 to 10 wherein R¹ and R² are both H. 12.4-[4-(methylsulfonyl)phenyl]-N-(pyridin-4-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;4-[4-(methylsulfonyl)phenyl]-N-(pyridin-3-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;4-[4-(methylsulfinyl)phenyl]-N-(pyridin-2-ylmethyl)-6-(trifluoromethyl)pyrimidin-2-amine;4-[4-(methylsulfonyl)phenyl]-N-(phenylmethyl)-6-(trifluoromethyl)-2-pyrimidinamine;N-(4-methoxybenzyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine;N-(4-fluorobenzyl)-4-[4-(methylsulfonyl)phenyll]-6-(trifluoromethyl)pyrimidin-2-amine;and pharmaceutically acceptable derivatives thereof.
 13. A process forthe preparation of compounds of formula (I) and pharmaceuticallyacceptable derivatives thereof as defined in any one of claims 1 to 12,which comprises: (A), reacting an amine HNR⁴(CR¹R²)_(n)-A of formula(II) or a protected derivative thereof with a compound of formula (III)

or a protected derivative thereof; or (B), reacting an alkyl halideHal-(CR¹R²)_(n)—A of formula (XII) or a protected derivative thereofwith a compound of formula (XIII)

or a protected derivative thereof; or (C), interconversion of a compoundof formula (I) into another compound of formula (I); or (D),deprotecting a protected derivative of a compound of formula (I); andoptionally converting compounds of formula (I) prepared by any one ofprocesses (A) to (D) into pharmaceutically acceptable derivativesthereof.
 14. A pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable derivative thereof asdefined in any one of claims 1 to 12 in admixture with one or morephysiologically acceptable carriers or excipients.
 15. A compound offormula (I) or a pharmaceutically acceptable derivative thereof asdefined in any one of claims 1 to 12 for use in human or veterinarymedicine.
 16. A method of treating a human or animal subject sufferingfrom a condition which is mediated by COX-2 which comprisesadministering to said subject an effective amount of a compound offormula (I) or a pharmaceutically acceptable derivative as defined inany one of claims 1 to
 12. 17. A method of treating a human or animalsubject suffering from an inflammatory disorder, which method comprisesadministering to said subject an effective amount of a compound offormula (I) or a pharmaceutically acceptable derivative thereof asdefined in any one of claims 1 to
 12. 18. The use of a compound offormula (I) or a pharmaceutically acceptable derivative thereof asdefined in any one of claims 1 to 12 for the manufacture of atherapeutic agent for the treatment of a condition which is mediated byCOX-2.
 19. The use of a compound of formula (I) or a pharmaceuticallyacceptable derivative thereof as defined in any one of claims 1 to 12for the manufacture of a therapeutic agent for the treatment of aninflammatory disorder.
 20. A compound of formula (I) or apharmaceutically acceptable derivative thereof as defined in any one ofclaims 1 to 12 for use in the treatment of a condition which is mediatedby COX-2.